This research program focuses on the characterization of redox enzymes with unusual cofactors, and their interactions with other electron transfer (ET) proteins. This includes enzymes that do not contain exogenous cofactors, but instead possess ?protein-derived cofactors? that are formed by multiple irreversible post-translational modifications of amino acid residues. This research has made major contributions to at least three areas of broad biological and biomedical significance: elucidation of mechanisms of biological ET; characterization of mechanisms of biosynthesis of protein-derived cofactors and their catalytic properties; and discovery of novel mechanisms of heme function and oxygen activation. The future goals include characterization of three novel classes of redox enzymes that we have recently identified. Lod-A like proteins possess a cysteine tryptophylquinone (CTQ) cofactor derived from specific cysteine and tryptophan residues. These are unusual as they are the first enzymes with tryptophylquinone cofactors that function as oxidases rather than dehydrogenases. They are also the first amino acid oxidases described that uses a cofactor other than a flavin for catalysis. LodB-like proteins are flavoenzymes that catalyze the post-translational modifications required for CTQ biosynthesis on a precursor LodA-like protein. These reactions must be performed by ?remote catalysis? that involves long-range ET, since the residues that are modified reside within the protein and are not surface exposed. As such, the mechanism of this process must be novel because no such reactions have been described that are catalyzed by a flavoenzyme, especially by remote catalysis. Rv2633c is a protein from Mycobacterium tuberculosis that is upregulated in response to the host defense during infection. It possesses two non-heme irons that are predicted from sequence to form an oxo-bridged hemerythrin-like site. We showed that this is the first hemerythrin-like protein to function as a catalase, and is the first example of a catalase with a non-heme di-iron cofactor. The results of these studies will further our understanding of the range and mechanisms of reactions that can be catalyzed by enzymes, particularly those involving oxygen reactivity and free radical intermediates. Understanding how enzymes control these reactive species during catalysis while minimizing oxidative damage will provide insights into how to mitigate the consequences of oxidative stress. This will also expand or current views about protein evolution and protein structure-function relationships, and provide insights for protein engineering strategies to introduce new functional groups into proteins.